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Gene Expression and Chromosomal Location for Susceptibility to Sjogren

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Gene Expression and Chromosomal Location for Susceptibility to Sjogren Journal of Autoimmunity 33 (2009) 99–108 Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm Gene expression and chromosomal location for susceptibility to Sjo¨gren’s syndrome Paola Pe´rez a,1, Juan-Manuel Anaya b,1, Sergio Aguilera c, Ulises Urzu´ a a, David Munroe d, Claudio Molina e, Marcela A. Hermoso a, James Michael Cherry d, Cecilia Alliende a, Nancy Olea a, Edward Ruiz-Narva´ez f, Marı´a-Julieta Gonza´lez a,* a University of Chile, Santiago, Chile b Center for Autoimmune Diseases Research (CREA), Corporacio´n para Investigaciones Biolo´gicas, Universidad del Rosario, Medellin, Colombia c INDISA Clinic-Andre´s Bello University, Santiago, Chile d National Cancer Institute, Bethesda, MD, USA e Mayor University, Santiago, Chile f Harvard School of Public Health, Boston, MA, USA article info abstract Article history: Primary Sjo¨gren’s syndrome (SS) is a chronic inflammatory autoimmune disease affecting mainly the Received 2 April 2009 exocrine glands. Its physio-pathology is poorly understood and most of the knowledge has been related Received in revised form to the inflammatory component. The aim of this work was to evaluate gene expression profiling in 11 May 2009 fractions enriched in epithelial cells from labial salivary glands (LSGs) of patients with primary SS and Accepted 19 May 2009 identify chromosomal regions harboring susceptibility genes expressed in epithelial cells. A combined approach of gene expression and genome-wide association study was used. Enriched epithelial cell Keywords: fractions were obtained from LSGs of patients and controls. Amplified total RNA was labeled and Sjo¨gren’s syndrome cDNA microarray hybridized to 10K cDNA microarrays. Results were normalized and subjected to statistical and functional Epithelial cells analysis. A genome-wide microsatellite screen at 10 cM resolution (393 markers) was performed. In Apoptosis salivary gland-epithelial cells from patients 528 genes were expressed differentially in comparison to Interferon controls. Pathways not previously linked to disease were found to be altered. Twenty-eight and 15 genes Genome-wide association study associated with apoptosis were up-regulated and down regulated, respectively. Interferon-related genes, most of which participated in interferon signaling, were also found to be up-regulated. From the genome-wide screen, 6 markers showed evidence of highly significant association with the disease. Of these, five loci harbor genes differentially expressed in patients LSG-epithelial cells. Our results show that in enriched gland-epithelial cells of pSS, both pro-apoptotic/anti-apoptotic and interferon signaling inhibition/stimulation balances may occur. Genes found over-expressed in epithelial cells are candidates for disease susceptibility. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction metalloproteinases (MMPs), mostly secreted by acinar and ductal cells but not related to the quantity and the proximity of mono- Sjo¨gren’s syndrome (SS) is a chronic autoimmune disease nuclear cells, have been demonstrated in labial salivary glands characterized by lymphocyte infiltration of the exocrine glands, (LSG) from SS patients [4–6]. Based on these findings three phases accompanied by autoantibody production [1]. A key event in the for the development of SS are proposed: first, a preexisting initial process leading to SS seems to be increased epithelial cell condition characterized by genetic susceptibility factors. Second, apoptosis that progresses to subsequent salivary gland lymphocytic a lymphocyte-independent phase which occurs as a consequence infiltration and autoantibody production [2,3]. High levels of matrix of antigens released by necrotic, apoptotic cells or viral trigger, activate innate immune response with cytokine production. Third, a tissue-specific immunological attack by activated T-cells, B-cells * Corresponding author at: Institute of Biomedical Sciences, Faculty of Medicine, and their products against corresponding self-antigens leads to University of Chile, Casilla 70061, Santiago 7, Chile.Tel.: þ56 2 9786017; fax: þ56 2 autoimmune exocrinopathy [1–3]. 737 3158. E-mail address: [email protected] (M.-J. Gonza´lez). The powerful impact of genetic predisposition on susceptibility 1 These authors contributed equally to this work. is usually based on disease concordance rates in monozygotic 0896-8411/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2009.05.001 100 P. Pe´rez et al. / Journal of Autoimmunity 33 (2009) 99–108 twins. Although genetic studies in primary SS twins have not been washed with Hanks’ balanced salt solution (Gibco BRL, Carlsbad, CA, performed the observed aggregation of autoimmune diseases in USA) and then centrifuged for 5 min at 1.9 Â gat4C. Washes were families of patients with primary SS supports a genetic component repeated from 3 to 12 times according to the extent of infiltration in SS etiology [7]. The efforts to unravel the genetic component of observed in each LSG biopsy until no lymphocytes were observed in SS have relied on association studies for disease gene identification. the supernatant or pellet. This was verified by direct microscopic However, robust analyses of candidate gene variants have not been observation of an aliquot of supernatant or pellet of epithelial cells. undertaken and only one linkage study has been reported [8]. In the The short-time, low-speed centrifugation and extensive washes absence of chromosomal regions identified by linkage studies, resulted in a pellet containing mostly epithelial (acini and ducts) research has focused on candidate gene approaches (by biological material. The final pellet was split to extract RNA for gene expression plausibility) rather than on positional approaches. To date, there is assays (see Section 2.3) and for morphological analysis as follows: not any specific gene for primary SS, and all of the polymorphisms aliquots were taken at each isolation step and fixed at 4 C for 18 h in associated with primary SS have been also associated with other a glutaraldehyde 2.5%-sodium caccodylate 0.1 M pH 7.4 buffer. Then, autoimmune diseases [9]. they were rinsed in a caccodylate buffer and post-fixed in a 1% DNA microarray technology allows gene expression information osmium tetroxide-0.1 M caccodylate buffer pH 7.4 for 1 h. Dehy- on a wide-genome basis to be obtained. A few reports have dration in graded series of ethanol was done before infiltration in an described transcriptional profiles of whole LSG from SS patients epoxy resin. Acinar fraction sections (1 mm) were obtained by means [10–12]. A neglected aspect of these studies is that the amount of of a Porter-Blum ultramicrotome (Sorvall MT-2, Thermo Electron mononuclear infiltrate in LSG varies between SS patients [13]. Corporation, Asheville, NC, USA) and stained with toluidine blue in Therefore, these gene expression profiles actually represent 1% sodium borate. In addition, the quality of the resultant cellular variable combinations of different cell types. To overcome the fractions was verified by reverse transcriptase-polymerase chain interference of infiltrated cells on epithelial cell gene expression, reaction (RT-PCR) [5] of marker genes such as: MS4A1, CD3G, ACTA2, we developed a method to obtain fractions enriched in epithelial and KRT18 as markers for B-lymphocytes, T-lymphocytes, myoepi- cells from LSGs and to determine their gene expression profiles thelial cells and acinar-ductal cells, respectively. Primers and using DNA microarrays. Through a genome-wide association study reaction conditions of each gene are described in Supplementary (GWAS) we next sought to identify chromosomal regions of SS data STable 2. susceptibility harboring expressed genes in LSG of SS patients. 2.3. RNA isolation, amplification and fluorescent cDNA labeling 2. Methods Total RNA was procured with the RNeasy Mini Kit (Qiagen, 2.1. Patients Valencia, CA, USA). Quality was verified with the Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA, USA). RNAs were All participating subjects were informed about the aims and amplified with the RiboAmp amplification kit (Arcturus, Sunnyvale, procedures of the present study and then signed a written consent CA, USA) following the supplier’s protocol. 2 mg of amplified RNA approved by the Ethics Committee of the School of Medicine, were labeled by reverse transcription in a 45 mL reaction containing University of Chile and the ‘‘Corporacio´ n para Investigaciones 1Â first strand buffer, 2 mg random primers, 2 mg oligo-dT, 0.5 mM Biolo´ gicas’’ (CIB), in Medellı´n, Colombia. All the patients met the of dATP, dGTP and dTCP, 0.2 mM dTTP, 0.08 mM of either Cy3 or Cy5 American-European diagnosis criteria for primary SS [14]. of dUTP, 0.01 mM dithiothreitol, and 500 U of SuperScript II enzyme For the microarray study, patients (n ¼ 9) were classified (Invitrogen, Carlsbad, CA, USA). After incubation at 42 C for 1 h, the according to the focus score (FS) [13]: FS 1–2 (n ¼ 2, age range reaction was halted with EDTA. Residual RNA was hydrolyzed with 43–60 years old, mean 51); FS 3–4 (n ¼ 3, age range 35–66 years NaOH at 65 C for 20 min. NaOH excess was neutralized by addition old, mean 48); FS higher than 4 (n ¼ 4, age range 35–64 years old, of Tris–HCl 1 M, pH 7.5 buffer. The labeled cDNA was purified by mean 54). Control subjects (n ¼ 6, age range 23–43 years old, mean ethanol precipitation in the presence of 20 mg of glycogen. Absor- 35) were selected from individuals not
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